Hydrogels are versatile carriers for carrier-linked prodrugs, see for example WO2006003014A2 and WO2011012715A1. As at least most of the drugs are connected to the inside of the hydrogel, they are protected from modifying and/or degrading enzymes present in a patient's body which extends the time period over which active drugs are released from such prodrugs.
However, once the drug is released from the hydrogel carrier, it is subject to renal clearance and exposed to modifying and/or degrading enzymes that reduce the half-life of the released drug.
To avoid this Harris (WO199922770) has devised hydrogel prodrugs which release biologically active moiety-poly(ethylene glycol) (PEG) conjugates. These prodrugs have two major disadvantages. On the one hand polymerization of the Harris' hydrogel occurs in the presence of drug molecules which get coupled to the forming hydrogel during polymerization. This may cause drug molecules to be entrapped in the hydrogel which may lead to a burst-type release of drug during hydrogel degradation.
On the other hand drug molecules are released upon degradation of labile bonds present in the hydrogel matrix. As the degradation process leads to fragments of various sizes, the exact nature of the PEG tag attached to the released biologically active moiety varies between different degradation products. The variable size of the PEG tags leads to different residual activities of the conjugates which are undesired from a pharmacological view point.